Non-syndromic cleft lip with or without cleft palate (CLplus/minusP) is one of the most common malformations of human structure. Despite numerous family and epidemiologic studies, few clues regarding the specific factors involved in the etiology of Clplus/minusP have been uncovered, and a consensus as to the most likely mode of inheritance has not been reached. Information on twins with CLplus/minusP would contribute greatly to our understanding of this trait. This information has, however, been difficult to obtain due to the relatively infrequent (approximately 1/40,000 livebirths) co-occurrence of CLplus/minusP and twinning. The proposed research will utilize an international network of ten twin registries to ascertain a large, unbiased sample (approximately 360 pais) of tins with Clplus/minusP. Zygosity of the same-sex pairs will be accurately assigned on the basis of microsatellite typing. Information on the familial and epidemiologic characteristics of CLplus/minusP in affected twins and their families will be collected. In addition, DNA from the twins, their affected siblings and the parents of affected sibling pairs will be stored. this will be the largest and most complete body of data on this unique and immensely important subsample of the CLplus/minusP population to date. This study will provide (1) unbiased estimates of MZ and DZ twin concordance rates, (2) an increased understanding of the mode of inheritance of CPplus/minusP, including improved estimates of the number and magnitude of effect of CLplus/minusP susceptibility loci and (3) an understanding of the genetic contribution to twin pair resemblance for CLplus/minusP. This study will also define the descriptive epidemiology of CLplus/minusP in twins and their families, and will help to determine if CLplus/minusP is associated with monozygotic and/or dizygotic twinning. Furthermore, the stored DNA will provide an important resource for characterizing and confirming linkage to alleged CLplus/minusP susceptibility loci. the results of this study will greatly increase our understanding of CLplus/minusP etiology, and will have direct implications for the design and interpretation of future analyses of CLplus/minusP. Thus, this study will ultimately influence the likelihood that the specific factors involved in the etiology of CLplus/minusP will be identified.